Division of Hematology/Oncology
600 Moye Blvd., Brody 3E127
Greenville, NC 27834
Position for a graduate student is currently available.
Stem cells have the ability to reproduce (i.e. selfrenewal) and to give rise to specialized cells (i.e. differentiation). Adult stem cells function as a reservoir for the replenishment of normal tissues and repair of damaged tissues. It is clear that genetic networks control the balance between self-renewal and differentiation, and that misregulation of these networks can result in overproliferation of adult stem cells and cancer. For several years, a increasing evidence supports the theory of cancer stem cells (CSCs) that tumor cells are heterogeneous containing rare tumor initiating cells (called by CSCs) and abundant non-tumor initiating cells. Furthermore, it has been proven that CSCs are similar to the stem cells in many aspects and exist in multiple cancer cells such as acute and chronic myeloid leukemia, breast cancer, and lung cancer. Therefore, specific therapies targeted at CSCs must be considered to increase the efficiency and safety of cancer treatment. The long-term objective of my laboratory is to unravel molecular mechanisms of cell fate reprogramming in vivo. Specifically, we focus on how stem cell regulators and small molecules control cell fate reprogramming in vivo and extend it by application of our findings to cancer stem cells (CSCs). We use the nematode Caenorhabditis elegans ( C. elegans) as a model system to study in vivo cell fate reprogramming. In C. elegans, germline stem cells (GSCs) persist throughout adulthood and replenish the germline with thousands of differentiated gametes. Importantly, a core network of conserved genes controls the balance between GSC renewal and differentiation. More importantly, some of conserved RNA regulators (e.g. STAR/KH domain protein GLD-1) have been implicated in the regulation of stem cell (or CSC) self-renewal and cell fate reprogramming in the C. elegans germ line. Therefore, C. elegans germline provides an attractive system for studying the reprogramming of CSCs. Our research plans include: (1) a focused analysis of the molecular mechanism of in vivo cell fate reprogramming, particularly dedifferentiation and transdifferentiation; (2) Identification and characterization of genetic regulators that contribute to reprogramming of stem cells (or CSCs) using a genetic/RNAi based-screening approach; (3) High-throughput screening of small molecules that induce cell fate reprogramming in C. elegans; (4) and the application of small molecule reprogramming in human disease models (e.g. leukemia). Notably, the C. elegans signaling pathways and genetic factors we plan to investigate are conserved throughout animal evolution. Thus, our work will provide mechanistic insight into the reprogramming process in humans and aid research into the prevention of human diseases, including cancers.
Aging is a complex process that is observed within an organism at genetic, molecular, and cellular levels, as well as can be defined as a gradual deterioration of physiological function. Although the fundamental mechanisms are still poorly understood, increasing evidence shows that a progressive and irreversible accumulation of oxidative stress caused by reactive oxygen species (ROS) impacts on the aging process and contributes to impaired physiological function, increased incidence of age-related disease, and shortened lifespan. Therefore, we here propose to investigate the impacts of genetic (e.g., Nrf2, Sirt1, and FOXO3a) and chemical factors on antioxidant defense mechanisms and age-induced stem cell senescence using both invertebrate and vertebrate model organisms, which may address fundamental biological questions regarding aging and development .
How cells acquire specific fates is a central question in developmental biology. Various processes including cell cycle and signaling pathways are crucial for developmental events in many systems, but are hard to integrate using existing modeling methodologies. Moreover, the molecular mechanism of how cell cycle regulators control specific developmental events remains largely unexplored. We are studying the molecular mechanism of how cell cycle regulators specify stem cell niche and stem cell fate using the nematode C. elegans as a model system.
Lee MH and Yoon DS (2016) A phenotype-based RNAi screening for Ras-ERK/MAPK signaling-associated stem cell regulators in C. elegans. Methods in Molecular Biology, In press.
Yoon DS, Pendergrass DL, and Lee MH (2016) A simple and rapid method for combining fluorescent in situ RNA hybridization (FISH) and immunofluorescence in the C. elegans germline. MethodsX. 3:378-385.
Lee MH , Mamillapalli SS, Keiper BD, and Cha DS (2016) A Systematic mRNA Control Mechanism for Germline Stem Cell Homeostasis and Cell Fate Specification. BMB Reports. 49(2): 93-98.
Seo HW, Cheon SM, Lee MH, Jeon H, and Cha DS (2015) Catalpol modulates lifespan via DAF-16/FoxO and SKN-1/Nrf2 activation in Caenorhabditis elegans. Evidence-Based Complementary and Alternative Medicine. 524878.
Polli J , Dobbins DL, Kobet R, Farwell MA, Zhang B, Lee MH, and Pan X (2015) Drug-Dependent Behaviors and Nicotinic Acetylcholine Receptor Expressions in Caenorhabditis elegans Following Chronic Nicotine Exposure , NeuroToxicology, 47: 27-36 .
Taki FA, Pan X, Lee MH, and Zhang B (2014) Nicotine exposure and transgenerational impact: a prospective study on small regulatory microRNAs. Scientific Reports. 4: 7513.
Kobet R, Pan X, Zhang B, Pak SC, Asch AS, and Lee MH (2014) Caenorhabditis elegans: A model system for anti-cancer drug discovery and therapeutic target identification. Biomolecules & Therapeutics. 22(5): 1-13.
Benson J, Cummings E, O'Reilly L, Lee MH*, and Pak S* (2014) A high-content assay for identifying small molecules that reprogram C. elegans germ cell fate. Methods , 68(3): 529-535. *Co-corresponding authors.
Lee MH*, Cha DS, Mamillapalli SS, Kwon YC, and Koo HS (2014) Transgene-mediated cosuppression of DNA Topoisomerase-1 gene in
International Journal of Biochemistry and Molecular Biology
.15:5(1): 11-20 *Corresponding author.
Datla, U.S., Scovill, N., Brokamp, A., Kim, E., Asch, A, and Lee, M.H. (2014) Role of PUF-8/PUF protein in stem cell control, sperm-oocyte decision and cell fate reprogramming. Journal of Cellular Physiology . 229(10): 1306-1311.
Kim, Y.S., Seo, H.W., Lee, M.H., Kim, D.K., Jeon, H., and Cha, D.S. (2013) Protocatechuic acid extends lifespan and increases stress resistance in Caenorhabditis elegans. Archives of Pharmacal Research 37(2):245-252.
Snow, J.J., Lee, M.H., Verheyden, J., Kroll-Conner, P.L., and Kimble, J. (2013) C. elegans FOG-3/Tob can either promote or inhibit germline proliferation, depending on gene dosage and genetic context. Oncogene 23; 32(21):2614-21.
Cha, D.S., Datla, U.S., Hollis, S.E., Kimble, J., and Lee, M.H. (2012) The Ras-ERK MAPK regulatory network controls dedifferentiation in Caenorhabditis elegans. BBA-Molecular Cell Biology 1823(10):1847-1855.
Cha, D.S., Hollis, S.E., Datla, U.S., Lee, S., Ryu, J., Jung, H.R., Kim, E., Kim, K., Lee, M., Li, C., and Lee, M.H. (2012) Differential subcellular localization of DNA topoisomerase-1 isoforms and their roles during Caenorhabditis elegans development. Gene Expression Patterns 12(5-6):189-195.
Whelan, J., Hollis, S., Cha, D., Asch, A., and Lee, M.H. (2012) Post-transcriptional regulation of Ras-ERK/MAPK signaling pathway. Journal of Cellular Physiology 227(3):1235-1241.
Lee, M.H.*, Kim, K.W.*, Morgan, C., Morgan, D., and Kimble, J (2011) The state of FOG- 3/Tob phosphorylation regulates initiation and maintenance of the Caenorhabditis elegans sperm fate program. Proc. Natl. Acad. Sci. USA 108(22):9125-9130. *equal contribution.
Lee, M.H.*, Hollis, S.E., Yoo, B.H., and Nykamp, K. (2011) Caenorhabditis elegans DNA-2 helicase/endonuclease plays a vital role in maintaining genome stability, morphogenesis, and life span. Biochem Biophys Res Commun . 407(3):495-500. *corresponding author.
Morgan, C.*, Lee, M.H.*, and Kimble J. (2010) Chemical reprogramming of Caenorhabditis elegans germ cell fate. Nature Chemical Biology 6(2): 102-104. *These authors contributed equally to this work.
Nykamp, K., Lee, M.H., and Kimble, J. (2008) C. elegans La related protein, LARP-1, localizes to germline P bodies and attenuates Ras-MAPK signaling during oogenesis. RNA 14(8):1550-7.
Lee, M.H., Hook, B., Pan, G., Kershner, A., Merritt, C., Seydoux, G., Thomson, J., Wickens, M., and Kimble J. (2007) Conserved Regulation of MAP Kinase Expression by PUF RNABinding Proteins. PLoS Genet . 3(12):e233.
Lee, M.H., Hook, B., Lamont, L.B., Wickens, M., and Kimble, J. (2006) LIP-1 phosphatase controls the extent of germline proliferation in C. elegans. EMBO J . 25: 88-96.
Lee, M.H., Han, S.M., Han, J.W., Kim, Y.M., Ahnn, J., and Koo, H.S. (2003) Caenorhabditis elegans dna-2 is involved in DNA repair and is essential for germ-line development. FEBS Lett . 555:250-256.
Jeong, Y.S., Kang, Y., Lim, K.H., Lee, M.H., Lee, J., and Koo, H.S. (2003) Deficiency of Caenorhabditis elegans RecQ5 homologue reduces life span and increases sensitivity to ionizingradiation. DNA Repair 2:1309-1319.
Lee, K.H., Lee, M.H., Lee, T.H., Han, J.W., Park, Y.J., Ahnn, J., Seo, Y.S., and Koo, H.S. (2003) Dna2 requirement for Normal Reproduction of Caenorhabditis elegans Is Temperature-dependent. Mol Cells 15(1):81-86.
Bandyopadhyay, J., Lee, J., Lee, J.I., Yu, J.R., Jee, C., Cho, J.H., Jung, S., Lee, M.H., Zannoni, S., Singson, A., Kim do, H., Koo, H.S., and Ahnn, J. (2002). Calcineurin, a calcium/calmodulin-dependent protein phosphatase, is involved in movement, fertility, egg laying, and growth in Caenorhabditis elegans. Mol Biol Cell 13(9):3281-3293.
Lee, M.H., Ahn B., Choi I.S., and Koo H.S. (2002) The gene expression and deficiency phenotypes of Cockayne syndrome B protein in Caenorhabditis elegans. FEBS Lett . 522:47-51.
Lee J., Jee C., Lee J.I., Lee, M.H., Lee M.H., Koo H.S., Chung C.H., and Ahnn J. (2001) A deubiquitinating enzyme, UCH/CeUBP130, has an essential role in the formation of a functional microtubule-organizing centre (MTOC) during early cleavage in C. elegans. Genes Cells 6(10):899-911.
Lee, M.H., Park H., Shim G., Lee J., and Koo H.S. (2000) Regulation of gene expression, cellular localization, and in vivo function of Caenorhabditis elegans DNA topoisomerase I. Genes Cells 6(4):303-12.
Lee, M.H., Jang Y.J., and Koo H.S. (1998) Alternative splicing in the Caenorhabditis elegans DNA topoisomerase I gene. Biochim Biophys Acta . 1396(2):207-14.
Young Scientists in the Lee Lab